When used for the treatment of endogenous depression, nortriptyline (NT), a monomethylated tricyclic antidepressant (TCA), demonstrates an upper therapeutic plasma level limit of approximately 150 ng/ml, above which response rate decreases. This finding has been corroborated in a number of studies which have retrospectively analyzed the relationship between therapeutic response and plasma NT levels. In addition, the phenomenon has been supported in a prospective controlled trial. There is a single report of a similar upper therapeutic plasma level limit for protriptyline, another monomethylated TCA. Finally, the Principal Investigator and co-workers have recently reported that desipramine (DMI), also a monodimethylated TCA, appears to show an upper therapeutic plasma level limit at 160 ng/ml. No dimethylated TCA has been observed to demonstrate an upper level effect. Consequently, for practical and theoretical reasons, it seems important to establish clearly if a second monomethylated TCA exhibits an upper therapeutic plasma level limit in a study wherein plasma level is under experimental control. Therefore, we propose to compare the rate of response of 40 subjects with endogenous depression (RDC) with steady-state plasma levels of DMI fixed between 100 and 150 ng/ml (Group A) 200 and 300 ng/ml (Group B) in a four week double-blind, controlled trial. It is predicted that Group A will have a significantly greater frequency of therapeutic response than Group B subjects. Group B will be divided into subgroups which have DMI dosages reduced to achieve DMI steady-state plasma levels of 100 to 150 ng/ml (Group B1) and those which continue on the same dosages of DMI (Group B2). It is predicted that after 3 weeks of additional treatment, nonresponders in Group B1 will demonstrate a greater frequency of response than nonresponders on Group B2.